The effects of chronic treatment with indapamide (3 mg/kg/day) on the structure and function of the mesenteric artery were studied in two groups of spontaneously hypertensive rats (SHRs) using an experimental model of in situ localized mesenteric artery. Indapamide (n = 12) or placebo (n = 12) were given to 8-week-old rats for 4 weeks. After anesthesia and laparotomy, a segment of mesenteric artery (external diameter, 300–400 μm) was exposed for video-microscopic measurements. The diameter-pressure relationships were established under active conditions (phenylephrine, 10−6M) and passive conditions (potassium cynanide. KCN) for transmural pressure ranging from atmospheric pressure to 200 mm Hg. These studied arterial segments were then fixed and their wall cross-sectional areas (CSA) measured in transverse sections. Active wall stress and tension were defined as the differences in wall stresses and wall tensions calculated for active and passive conditions. Systolic arterial pressure and mesenteric CSA were decreased in treated rats (197 ± 15 mm Hg vs. 211 ± 12 mm Hg. p > 0.05; 16.230 ± 1048 μm2 vs. 19.033 ± 1082 μm2, p > 0.05). In both groups, mesenteric diameters were smaller under active than under passive conditions without significant differences in treated vs. untreated group under active conditions. The active wall tension was lower in treated (0.4 ± 0.19 N/m) than in untreated rats (1.19 ± 0.62 N/m. p > 0.05). However, there were no differences in active wall stress in both groups (103 ± 47 kPa and 134 ± 30 kPa). These results suggest that chronic treatment with indapamide induced a reduction of the mesenteric arterial smooth-muscle mass associated with a marked decrease in its maximal contractile tone. The latter was related to the smooth-muscle mass reduction and not to alteration of the vascular muscle contractility.

OBJECTIVEThe aim was to compare the effects of two diuretics, indapamide and hydrochlorothiazide, on cardiac hypertrophy in stroke prone spontaneously hypertensive rats (SHR-SP).METHODSSix week old SHR-SP, on a 1% sodium chloride water intake, were treated with oral indapamide (3 mg.kg-1 x d-1) or hydrochlorothiazide (20 mg.kg-1 x d-1) over a 44 d period. The hypertrophic process was evaluated by classical indices and by the morphological analysis of myocyte cross sectional area, coronary artery thickness, and immunohistochemical analysis of interstitial fibrosis.RESULTSIn the untreated SHR-SP on 1% sodium chloride, all animals developed severe hypertension and cardiac hypertrophy when compared to normotensive salt loaded WKY by 13 weeks of age. In salt loaded SHR-SP treated with indapamide or hydrochlorothiazide, systolic blood pressure was moderately decreased by the end of the treatment when compared with untreated SHR-SP, at 259(7) and 245(7) mm Hg respectively, v 300(11) mm Hg, p < or = 0.05. Myocyte enlargement appears to be the main feature involved in the development of cardiac hypertrophy in the SHR-SP. By the end of treatment both indapamide and hydrochlorothiazide prevented the development of cardiac hypertrophy evaluated by heart weight to body weight ratio [4.69(0.07) and 4.61(0.08) respectively, v 5.39(0.13), p < or = 0.001] and myocyte hypertrophy (-33% and -21% of the SHR-SP values, p < or = 0.001). Myocardial interstitial fibrosis and perivascular fibrosis were practically absent in the two treated groups.CONCLUSIONSOur results allow the characterisation of SHR-SP cardiac hypertrophy and indicate that the two types of chronic diuretic treatment prevent SHR-SP cardiac hypertrophy with a drug specific efficiency.

The effects of two diuretics, indapamide (3 mg/kg/day) and hydrochlorothiazide (20 mg/kg/day), were analyzed over a 44-day period on the cardiovascular hypertrophy of stroke-prone spontaneously hypertensive rats (SHR-SP). Untreated SHR-SP developed severe hypertension and cardiac hypertrophy when compared to normotensive Wistar-Kyoto (WKY) rats after 8 weeks on 1% sodium chloride. In diuretic-treated animals, systolic blood pressure was moderately decreased by the end of the treatment when compared with untreated SHR-SP (- 13 and - 18%. respectively, p < 0.05). Morphometric analysis of myocyte cross-sectional areas evidenced that indapamide was the most effective in preventing myocyte hypertrophy ( −33%, p < 0.0001). Small coronary artery wall thickness was efficiently prevented in the two treated groups, but medial hypertrophy was prevented by hydrochlorothiazide only. Among markers of smooth-muscle cell phenotype (contractile or extracellular matrix proteins) EIIIA-fibronectin (FN), one FN cellular isoform, was shown to be the most sensitive marker by an immunohistochemical technic. Medial expression of EIIIA-FN, which was characteristic of SHR-SP coronary arteries, was prevented by the two treatments. The two diuretic treatments, despite similar effects on blood pressure and smooth-muscle phenotype, prevent SHR-SP cardiovascular hypertrophy with a drug-specific efficiency.

Cerebral ischemia occurs frequently and is disabling. In addition to preventing and correcting risks factors, drugs prevent cell death induced by ischemia-hypoxia. Precise knowledge of the pathophysiology of cerebral ischemia is the prerequisite for drug development, and the main proofs of efficiency are histopathological and clinical (i.e., the results of controlled studies). Different animal models are considered valid for global, focal, or multifocal ischemia. These models have enabled the identification of deleterious phenomena that could be corrected or neutralized by drugs: hypoxia, lactic acidosis, release of neurotransmitters, influx of calcium, activation of phospholipase A2, release of excitatory amino acids, excess of free radicals, and neuronal cell metabolic paralysis (decrease of oxygen and glucose consumption). The chronology of these events clearly described herein will prompt the choice of the best drug, based on the delay between the ischemic event and the decision to treat. The main pharmacological effects required are the following: antagonism of hypoperfusion, oxygenation improvement, blockade of calcium influx and neurotransmitters action, reduction of acidosis and potassium efflux, blockade of arachidonic cascade and free radicals production, and antiedematous effect. The analysis of almitrine-raubasine (Duxil) pharmacological properties will be used as an example of these potentially anti-ischemic drugs. Almitrine-raubasine pharmacological studies indicate that this drug has several beneficial effects on cerebral ischemic processes. These studies have dealt with effects of hypobaric hypoxia on deoxyglucose uptake in the rat, protective effects on permanent or temporary cerebral ischemia-induced neurobehavioral problems in the gerbil, and preservation of the glycogen content and of the swelling in astrocytes after bilateral occlusion of the carotid arteries in the rabbit.

During recent years many studies on the electroencephalogram (EEG) changes induced by almitrine-raubasine (Duxil) have been performed in elderly patients and in animals. This article gives an overview of three questions raised by their results. Is there a simple addition of the raubasine and almitrine effects when they are coadministered? Are the EEG effects of this treatment dependent on the patient's disease? To what extent could EEG studies provide some knowledge about the mechanism of action of almitrine-raubasine therapy? In adult (8 months) and aged (22 months) rats the EEG changes induced by the coadministration of almitrine and raubasine were significantly different from the addition of individual almitrine and raubasine EEG effects. In adult rats the coadministration induced slighter EEG changes than those predicted by the addition of almitrine and raubasine effects. In aged rats, the coadministration induced a decrease in delta-theta power not predictable from the effects of almitrine or raubasine. These results could be taken as an indication that some biological targets are common for the two drugs and that the coadministration results in pharmacological effects more complicated than a simple addition of raubasine and almitrine properties. After 3 weeks of treatment in aged healthy subjects, the coadministration induced an increase in the alpha and beta power with a slight decrease of delta and beta-1 powers. In patients with cognitive decline of probable degenerative origin, 3 months of therapy with almitrine-raubasine was mainly associated with a decreased delta and theta power and a slight increase in high frequency components of the alpha band.(ABSTRACT TRUNCATED AT 250 WORDS)